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Less Cardiac Risk, Toxicity With Reformulated Doxorubicin For Metastatic Breast Cancer

Single-agent liposome-encapsulated doxorubicin (TLC D-99) produces less cardiotoxicity than conventional doxorubicin while providing comparable anti-tumour activity in the first-line treatment of women with metastatic breast cancer.

Although doxorubicin, a widely used anthracycline glycoside with applications as an antineoplastic agent, has proved to be one of the most effective breast cancer chemotherapies, it can damage individual muscles and blood vessels of the heart, posing a five percent risk of heart failure at maximum approved dose. A formulation in which it is surrounded by protective oils - liposomes - reduces that risk because blood can flow through the heart without dissolving.

Investigators at institutions throughout the United States and in Canada enrolled 224 patients of median age 54 years with metastatic breast cancer and no prior therapy for metastatic disease. The patients were randomised to receive either TLC D-99 75 mg/mē or conventional doxorubicin 75 mg/mē every three weeks, unless disease progressed or toxicity became unacceptable.

The primary efficacy endpoint was response rate, with responses required to last for six weeks. The primary safety endpoint was cardiotoxicity.

Patients were removed from the study if left ventricular ejection fraction fell by 20 ejection fraction units or more from baseline to a final value exceeding or equal to 50.0 percent, or by 10 or more units to a final value of less than 50.0 percent, or at onset of clinical congestive heart failure.

All relevant prognostic factors were balanced between the two treatment groups, except that there were significantly more patients who were progesterone receptor-positive in the conventional doxorubicin-treated group.

Protocol-defined cardiotoxicity occurred in 13.0 percent of TLC D-99 patients (including two cases of congestive heart failure). This was less than half the rate (29.0 percent) of cardiotoxicity among conventional doxorubicin patients (including nine cases of congestive heart failure).

The median cumulative doxorubicin dose at onset of cardiotoxicity was significantly greater for TLC D-99 (785 mg/mē) than for conventional doxorubicin (570 mg/mē). The overall response rate was 26.0 percent in both treatment groups.

The median time to progression was 2.9 months on TLC D-99 versus 3.1 months on doxorubicin. Median survival showed a non-significant trend in favour of conventional doxorubicin (20 months) compared with TLC D-99 (16 months).

Clinical toxicities besides irreversible heart damage that have been associated with doxorubicin, such as severe nausea and vomiting, esophageal and intestinal ulcers and bone marrow suppression, appeared less often with TLC D-99, but this difference was not statistically significant.
Cancer 2002; 94(1):25-36. "Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma"

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